Drugs administered orally can be absorbed through the oral mucosa, through the lining of the stomach and primarily through the small and large intestines; however, the rate of absorption depends on the ability of the drug to pass through the lipid barrier of epithelial membranes. For example, alcohol, a lipid soluble, non-ionic compound, is rapidly absorbed into the blood stream by diffusion across the gastric mucosa. Weak acids are also well absorbed through the lining of the stomach, while weak bases are absorbed mainly in the small intestine. Drugs that are ionized, or lipid insoluble, for example, quaternary ammonium compounds and streptomycin, are poorly absorbed in the digestive tract, and must be administered by injection. Although injected drugs are not subject to the gastrointestinal barriers to bioavailability which are imposed on drugs administered orally, nonetheless, minimal tissue uptake or lack of tissue retention often interfere with the injected drug's bioavailability.
Under normal circumstances, intact dietary lipids, mostly triglycerides and phospholipids, are not readily absorbed through the intestinal mucosa. Phospholipids are present physiologically in the gut as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol and phosphatidic acid. The normal physiological mechanism for lipid absorption requires conversion of the phospholipid to lysophospholipids by removal of the sn-2 acyl group by the hydrolytic action of the pancreatic enzyme phospholipase A2 on the sn-2 acyl ester bond. Conversion of phospholipids to lysophospholipids provides the normal mechanism for absorption and transport of this class of lipids from the gut and accounts for the uptake of several grams of phospholipid per day.
While the need continues for less toxic, more selective, and more effective prodrugs of all types, bioavailability of pharmaceutical agents remains an important problem. Many oral drug candidates fail because of difficulty in oral absorption or in penetration of the cellular membranes of target tissues in the body after injection. Many intravenous, intraperitoneal, or other injectable drug candidates fail because of difficulty in penetrating cellular membranes of target tissues and/or failure to be retained in the tissue.
For example, the antiviral compounds phosphonoacetate and phosphonoformate, which were first synthesized in 1924 (Nylén, Chem. Berichte 57:1023), have the ability to inhibit viral enzymes selectively. This ability was not immediately demonstrated. Helgstrandi, et al., Science 201:819-821 (Sep. 1, 1978) disclosed that both phosphonoacetic acid and phosphonoformic acid inhibit several DNA polymerases and preferentially inhibit several viral DNA polymerases. Phosphonoformate and phosphonoacetate are presently known to selectively inhibit the DNA polymerase of many viruses, including human cytomegalovirus (HCMV), herpes simplex virus (HSV) and the reverse transcriptase of human immunodeficiency virus (HIV). Chrisp and Clissold ((1991) Drugs 41:104) review the pharmacology of these agents. Phosphonoacetate is too toxic for use in humans, but phosphonoformate (Foscavir, Astra) is approved for human use in HCMV-infected AIDS patients. However, it is not highly potent, requires prolonged intravenous administration and has substantial toxicity to the kidney and other organs. Ericksson, et al., U.S. Pat. Nos. 4,215,113; 4,339,445; 4,665,062; 4,771,041 teach the use of phosphonoformic acid as the selective agent in treating viral infections, including herpes virus type I and II and cytomegalovirus, in treating cancer caused by virus, and also opposing transformation of cells caused by oncogenic viruses.
Derivatized forms of phosphonoacids and pharmaceutical formulations comprising these compounds are known. U.S. Pat. No. 5,072,032 to McKenna discloses thiophosphonoacids; U.S. Pat. Nos. 4,386,081 and 4,591,583 to Helgstrand et al. disclose phosphonoformic acid esters of alkyl, alkylene, alkoxy and related cyclic and aromatic groups and some of these are shown to inhibit herpes virus and the functions and intracellular multiplications of influenza virus. U.S. Pat. No. 5,194,654 to Hostetler et al., discloses phospholipid derivatives of phosphonoacids, their incorporation into liposomes and their use as selective antiviral and antiretroviral agents.
It would be useful to identify chemical structures for pharmaceutical prodrugs which enhance oral bioavailability and/or cellular uptake and retention regardless of the route of administration. The optimized prodrugs would be metabolized in target tissues to release the pharmaceutical agent, which agent would persist in the target tissue to exert its intended action either directly or after metabolic conversion to the active form.